Chromatin proteins and modifications as drug targets

Helin, Kristian; Dhanak, Dashyant

doi:10.1038/nature12751

Cited by 388 publications

(348 citation statements)

References 98 publications

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“…Therefore, novel therapeutic strategies effectively interfering with metastatic spread are required. Recently, several chromatin-modifying drugs have been successfully applied in preclinical cancer models and are likely to be taken forward to clinical trials 60 . Accordingly, our study reveals that EZH2 inhibition might be a promising strategy for future therapies of human melanoma patients.…”

Section: Discussionmentioning

confidence: 99%

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

et al. 2015

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Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.

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Section: Discussionmentioning

confidence: 99%

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

et al. 2015

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“…The epigenetic drugs acting to regulate chromatin remodeling and gene transcription have gained considerable recognition in the treatments of various types of cancers, 19,20 neurologic disorders, 21 HIV infections, 22 cardiovascular and inflammatory diseases, 23 and others. To systematically screen for the epigenetic effects on CLDN14 gene expression, we treated the primary cultures of mouse TALH cells (freshly isolated from the C57BL/6 mice described before) 9,10 in vitro for 16 hours with the DNA methyltransferase inhibitor 5-Aza-29-deoxycytidine, the histone-lysine methyltransferase inhibitor BIX 01294, 24 the histone demethylase inhibitor tranylcypromine, 25 and the HDAC inhibitors trichostatin A (TsA) and suberanilohydroxamic acid 26 (SAHA; approved by the Food and Drug Administration as Vorinostat).…”

Section: An Epigenetic Program Regulates the Mir-cldn14 Axis In The Kmentioning

confidence: 99%

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Gong

Himmerkus

Plain

et al. 2015

Journal of the American Society of Nephrology

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The kidney has a major role in extracellular calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney-claudin-14, -16, and -19-as critical for calcium imbalance diseases. Despite the compelling biologic evidence that the claudin-14/16/19 proteins form a regulated paracellular pathway for calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of therapies to correct calcium transport abnormalities. Here, we report that treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice. Furthermore, treatment of mice with HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that HDAC inhibitors transiently increase the paracellular cation conductance in the thick ascending limb. Genetic ablation of claudin-14 or the use of a loop diuretic in mice abrogated HDAC inhibitor-induced hypocalciuria. The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with antagomiRs against these miRs relieved claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases.

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“…While initially histone lysine methylation was found to be an essential chromatin mark, later work also showed lysine methylation of several non-histone proteins [1][2][3][4] . The sequential transfer of methyl groups from S-adenosyl-L-methionine to the ε-amino group of lysine residues is catalyzed by a family of enzymes called Protein Lysine Methyltransferases (PKMTs) that contains over 60 proteins in the human genome.…”

Section: Introductionmentioning

confidence: 99%

Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays

Kudithipudi

Kusević

Weirich

et al. 2014

JoVE

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Lysine methylation is an emerging post-translation modification and it has been identified on several histone and non-histone proteins, where it plays crucial roles in cell development and many diseases. Approximately 5,000 lysine methylation sites were identified on different proteins, which are set by few dozens of protein lysine methyltransferases. This suggests that each PKMT methylates multiple proteins, however till now only one or two substrates have been identified for several of these enzymes. To approach this problem, we have introduced peptide array based substrate specificity analyses of PKMTs. Peptide arrays are powerful tools to characterize the specificity of PKMTs because methylation of several substrates with different sequences can be tested on one array. We synthesized peptide arrays on cellulose membrane using an Intavis SPOT synthesizer and analyzed the specificity of various PKMTs. Based on the results, for several of these enzymes, novel substrates could be identified. For example, for NSD1 by employing peptide arrays, we showed that it methylates K44 of H4 instead of the reported H4K20 and in addition H1.5K168 is the highly preferred substrate over the previously known H3K36. Hence, peptide arrays are powerful tools to biochemically characterize the PKMTs. Video LinkThe video component of this article can be found at

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Chromatin proteins and modifications as drug targets

Cited by 388 publications

References 98 publications

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays

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